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Behavioral Pharmacology: What it was, is, and might be. Marc N. Branch University of Florida. One of the enduring problems in drug therapeutics is variation in drug response. Both within and across subjects Especially prominent in psychiatry – “Try this”

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Behavioral pharmacology what it was is and might be l.jpg

Behavioral Pharmacology: What it was, is, and might be.

Marc N. Branch

University of Florida


One of the enduring problems in drug therapeutics is variation in drug response l.jpg
One of the enduring problems in drug therapeutics is variation in drug response.

  • Both within and across subjects

  • Especially prominent in psychiatry – “Try this”

  • Promise of pharmacogenomics – genetically tailored treatment.

  • Behavioral pharm may also provide useful information


Origins l.jpg
Origins variation in drug response.

  • Chlorpromazine in the 1950’s

  • Beginnings of Psychopharmacology

  • Early results

    • Behavior -specific drug effects (e.g., CPZ avoid/escape)


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Syllogism variation in drug response.

  • Major premise: Different behavior affected differently by drug

  • Minor premise: Different behavior results from different experience

  • Conclusion: Different experience can produce different drug effects


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Study that founded B. Pharm. variation in drug response.

  • Dews, 1955

  • Pigeons – trained to peck key by having key pecks result in food presentation

  • Two behavioral conditions

    • 1. Every 50th peck resulted in food presentation

    • 2. First peck every 15 min resulted in food presentation

  • Test various doses of sodium pentobarbital



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Isolated-organ preparations variation in drug response.


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Compatibility of EAB and Pharmacology variation in drug response.

  • Isolated organ – isolated behavior

  • Highly controlled environments

  • Baseline, permits ABA design (B = drug)

    • Easy replication

    • Easy dose-response analysis

  • Automatic real-time measurement


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Early important contributions variation in drug response.

  • Schedule vs. Motivational Effects

  • Rate-dependency

  • Behavioral Tolerance


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Kelleher and Morse (classic) variation in drug response.

  • Squirrel Monkeys

  • Lever press

  • Multiple FR30 FI10-min

  • SR = food or escape from shock-stimulus complex


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Baseline performance variation in drug response.


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Drug effects variation in drug response.


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What is it about schedules? variation in drug response.

  • It’s not what the behavior is

  • It’s not what the schedule delivers

  • Schedules do produce different rates and temporal patterns.

  • First option is rates of responding.

    • Feat of experimental economy with a single FI schedule

    • Get 10 rates from one schedule!


Voila l.jpg
Voila! variation in drug response.


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Give drug to animal responding under an FI schedule variation in drug response.

  • Amazingly orderly result.


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Lots of interest in this phenomenon variation in drug response.

  • Under FI, many drugs, from many classes, produced this effect.

  • Too many different drugs?

  • Dews’ seminal experiment went the other way – high FR rates up while lower FI rates down.

  • What about those FI (supposed) rates?


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New interpretation variation in drug response.

  • Drug disrupts temporal organization.

  • More evident when re-plotted as rate against rate


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As rate-dependency’s reach was seen as ever more restricted, a void developed. If response-rate is not the “cause” of drug effects, what is? Because there were no obvious answers, the field moved in other directions.


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One direction, which was consistent with the original emphasis on the role of behavioral factors in drug effects, was the study of tolerance to behavioral effects of drugs.


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Seminal experiment here was by Schuster, Dockens, and Woods emphasis on the role of behavioral factors in drug effects, was the study of tolerance to behavioral effects of drugs.

  • Rats under mult FI 30-s DRL 30-s

  • Amphetamine daily for 30 sessions


Main result l.jpg
Main result emphasis on the role of behavioral factors in drug effects, was the study of tolerance to behavioral effects of drugs.


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Led to a general technique emphasis on the role of behavioral factors in drug effects, was the study of tolerance to behavioral effects of drugs.

  • B-A procedure

    • Usually between group

    • One group gets drug repeatedly before sessions

    • Other gets same dose after sessions (equates drug exposure)

    • Group A, then gets drug before session

  • Logic is that if drug-behavior interaction is necessary for tolerance, groups should differ. Only B got it.


Example carlton wolgin l.jpg
Example: Carlton & Wolgin emphasis on the role of behavioral factors in drug effects, was the study of tolerance to behavioral effects of drugs.


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Followed by other analyses, e.g. Smith emphasis on the role of behavioral factors in drug effects, was the study of tolerance to behavioral effects of drugs.


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The other research directions, however, emphasized stimulus functions of drugs, specifically reinforcing and discriminative. A great deal of work focused on drug self-administration (drugs as reinforcers) and drug discrimination (drugs as SDs).


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Drug discrimination – basic procedure functions of drugs, specifically reinforcing and discriminative. A great deal of work focused on drug self-administration (drugs as reinforcers) and drug discrimination (drugs as S

  • Two manipulanda

  • One is “hot” (usually FR sched of SR), other is not (EXT)

  • Which is hot in a given session depends on whether drug or vehicle was given before session.

  • Basically a 2-response multiple schedule with components alternating between sessions.


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Miraculous Effects Emerge functions of drugs, specifically reinforcing and discriminative. A great deal of work focused on drug self-administration (drugs as reinforcers) and drug discrimination (drugs as S

  • Not so miraculous – train with one dose, others show generalization


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More miraculous- functions of drugs, specifically reinforcing and discriminative. A great deal of work focused on drug self-administration (drugs as reinforcers) and drug discrimination (drugs as S Train with one drug, and others known to interact at same receptor (determined in vitro) generalize!


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What is miraculous? functions of drugs, specifically reinforcing and discriminative. A great deal of work focused on drug self-administration (drugs as reinforcers) and drug discrimination (drugs as S

  • Drugs known to bind to different receptors are not generalized to! Animal responds like it’s vehicle!

  • Why is that amazing?

    • Complexity of neurophysiology

    • Downstream effects

    • Organization of systems


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Can do “real” pharmacology functions of drugs, specifically reinforcing and discriminative. A great deal of work focused on drug self-administration (drugs as reinforcers) and drug discrimination (drugs as S


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Why the downturn over the past decade? functions of drugs, specifically reinforcing and discriminative. A great deal of work focused on drug self-administration (drugs as reinforcers) and drug discrimination (drugs as S

  • It really is as complicated as it seems it ought to be.

  • Example:

    * % rats showing ≥ 80% choice of EtOH Lever


Self administration l.jpg
Self-administration functions of drugs, specifically reinforcing and discriminative. A great deal of work focused on drug self-administration (drugs as reinforcers) and drug discrimination (drugs as S


Much continuing research l.jpg
Much continuing research functions of drugs, specifically reinforcing and discriminative. A great deal of work focused on drug self-administration (drugs as reinforcers) and drug discrimination (drugs as S

  • Face Validity

  • Drugs can serve as reinforcers

  • Abuse-liability assessment

  • Model of drug abuse – examine factors that influence SA

    • Alternative reinforcers

    • Punishment (interestingly, not much work here)

    • Measure reinforcing effectiveness: choice, PR, demand



What bp might be l.jpg
What BP might be influence drug action?

  • Renewed focus on behavioral factors

  • How can that be done in apparent absence of theoretical base?

    • SA continues on face validity

    • DD has pharmacology and receptor theory guiding it

  • One possibility, suggested long ago (Thompson and Schuster, 1968) is to focus on “Behavioral Mechanisms of Action”


Definition l.jpg
Definition influence drug action?

“By behavioral mechanism of drug action, we refer to a description of a drug's effect on a given behavioral system expressed in terms of some more general set of environmental principles regulating behavior.” (Thompson, 1981)


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Clarifying(?) analogy influence drug action?

  • Drug affects blood presssure

    • What factors NORMALLY control blood pressure?

      • Heart rate

      • Stroke volume

      • Peripheral resistance

      • Baroreceptor reflexes

      • Fluid balance


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  • Suppose drug influence drug action?just decreases stroke volume. If so, it’s mechanism of action in reducing blood pressure would be that it reduces stroke volume.

  • Suppose it just decreased peripheral resistance; then the lowering of pressure would be by decreasing peripheral resistance.

  • In either case, as the “justs” show, need to measure drug’s interaction with each of the known possible contributors.


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For BP, consider the following (until you hit the basic physics). For example, what are mechanisms involved reducing stroke volume? That would/could involve understanding heart-muscle mechanics.


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Behavior is usually complexly determined. (until you hit the basic physics). For example, what are mechanisms involved reducing stroke volume? That would/could involve understanding heart-muscle mechanics.

  • We know of many, as previous slide indicates, possible influences.

  • They all have to be tested for as complete a characterization as possible.

  • It will be time consuming, but there is no way around it.

  • Regrettably, even the most basic of findings has yet to be subjected to such an examination (e.g., Dews, 1955)


Two advantages of making the effort l.jpg
Two advantages of making the effort (until you hit the basic physics). For example, what are mechanisms involved reducing stroke volume? That would/could involve understanding heart-muscle mechanics.

  • May well provide an improved understanding of the origins of variation in drug response (original problem).

  • Is likely to improve our “list” of possible controlling variables (i.e., BP research can inform behavioral research)


Some brief examples of the latter l.jpg
Some brief examples of the latter (until you hit the basic physics). For example, what are mechanisms involved reducing stroke volume? That would/could involve understanding heart-muscle mechanics.

  • Is punishment a unitary process?


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McKearney, 1976 (until you hit the basic physics). For example, what are mechanisms involved reducing stroke volume? That would/could involve understanding heart-muscle mechanics.

  • Established FI performance with either food or termination of shock-stimulus-complex as reinforcement.

  • Added electric-shock punishment

  • Tested effects of doses of sodium pentobarbital and d-amphetamine


Branch et al 1977 l.jpg
Branch et al., 1977 (until you hit the basic physics). For example, what are mechanisms involved reducing stroke volume? That would/could involve understanding heart-muscle mechanics.

  • Pigeons; key pecking maintained by mult RI 1 min RI 6 min food.

  • Added RR 3 TO (20-s) , or RR 3 of 100-ms shock to RI 1

  • Tested effects of NaPB


Overall summary l.jpg
Overall summary (until you hit the basic physics). For example, what are mechanisms involved reducing stroke volume? That would/could involve understanding heart-muscle mechanics.

  • BP began with many dramatic demos of behavioral modification of drug action.

  • Showed weaknesses of simplistic accounts (e.g., motivational)

  • Rate-dependency emerged as organizing principle

  • As rate-dependency’s limitations became evident, research moved to DD and SA

  • DD is fading, SA continues

  • Where to? Suggestion here is behavioral mechanisms of action.


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